Coronary heart disease (CHD) is the most common cause of death in the United States. Traditional risk factors, such as smoking and hypertension, do not account for all of the risks in the development of heart disease. Recently, research has demonstrated that depression, which affects 16-23% of patients suffering heart attacks, is an important factor that affects the risk of death in patients with coronary heart disease. Brain regions involved in depression and stress may mediate the increased risk of cardiac mortality in depression. We have developed a model of brain areas including anterior cingulate and hippocampus, through either direct or indirect pathways through cortisol and the sympathetic system to the heart, mediating an increased risk for cardiac mortality. We have developed techniques to perform simultaneous imaging of the heart and brain, as well as measurement of the stress hormones cortisol and norepinephrine, during a stress challenge in patients with heart disease, with and without depression. Preliminary data shows decreased hippocampal and anterior cingulate activation with a stressful challenge in CHD patients with depression. Patients with CHD and depression showed a pattern of greater stress induced myocardial ischemia. Specific Aims of this proposal are therefore to: 1) Use positron emission tomography (PET) and O-15 water to measure brain correlates of a stressful cognitive challenge in patients with heart disease, with and without depression; 2) Inject [Tc-99m]sestamibi at the time of the stress challenge and image myocardial perfusion with single photon emission tomography (SPECT) in the same subjects; 3) Assess the effects of stress on cortisol and norepinephrine as well as heart rate variability as mediators of the effects of the brain on myocardial function. Secondary aims are to assess the effects of early life trauma on brain and heart activation, to compare mental stress and exercise stress induced myocardial ischemia, and to assess the effects of high intensity white matter lesions on T2 weighted MRI. Hypotheses are that CHD patients with depression will show decreased hippocampal and anterior cingulate function during stress which will be associated with myocardial ischemia and decreased heart rate variability. PUBLIC HEALTH RELEVANCE Depression in CHD is associated with increased mortality; understanding mechanisms involved may lead to new treatments with the potential to reduce CHD mortality. Narrative This project uses positron emission tomography (PET) measurement of brain function and single photon emission tomography (SPECT) imaging of heart function during a stressful task to look at mechanisms by which depression increases the risk of mortality from cardiovascular disease (CVD). The project will measure changes in brain function that occur during stress and the way these may affect myocardial ischemia in patients with CVD and depression, as well neurohormonal changes that may mediate these effects. Understanding brain-based mechanisms by which depression increases mortality from CVD has the potential to lead to new treatments for this disorder.